Synthesis of Fusidic Acid Derivatives Yields a Potent Antibiotic with an Improved Resistance Profile.
Synthesis of Fusidic Acid Derivatives Yields a Potent Antibiotic with an Improved Resistance Profile.
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DOI：
10.1021/acsinfecdis.0c00869
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发表时间：
2021-02-12
影响因子：
5.3
通讯作者：
Hergenrother PJ
中科院分区：
文献类型：
--
作者：
Garcia Chavez M;Garcia A;Lee HY;Lau GW;Parker EN;Komnick KE;Hergenrother PJ
福西地酸（FA）是一种强效类固醇抗生素，在欧洲已经使用了60多年，用于治疗革兰氏阳性病原体引起的各种感染。尽管其临床成功，但FA需要显著增加剂量（第一天3 g，随后几天1.2 g）以最大限度地减少耐药性，因为FA显示出高耐药频率，并且对耐药细菌的最低抑制浓度有很大的变化。尽管在这些方面进行了改进，但所有先前构建的FA衍生物对革兰氏阳性菌的抗菌活性都比母体天然产物差。在这里，我们报告了一种新的FA类似物的创建，它对金黄色葡萄球菌（S. aureus）和屎肠球菌（E. faecium）的临床分离株具有相同的效力，并且与FA相比，在体外具有更好的耐药性。重要的是，这种新化合物在软组织小鼠感染模型中显示出对fa耐药金黄色葡萄球菌菌株的有效性。这项工作描述了FA的结构特征，这是有效的抗生素活性所必需的，并证明了这种支架和靶点的耐药谱可以得到改善。
Fusidic acid (FA) is a potent steroidal antibiotic that has been used in Europe for more than 60 years to treat a variety of infections caused by Gram-positive pathogens. Despite its clinical success, FA requires significantly elevated dosing (3 g on the first day, 1.2 g on subsequent days) to minimize resistance, as FA displays a high resistance frequency, and a large shift in minimum inhibitory concentration is observed for resistant bacteria. Despite efforts to improve on these aspects, all previously constructed derivatives of FA have worse antibacterial activity against Gram-positive bacteria than the parent natural product. Here, we report the creation of a novel FA analogue that has equivalent potency against clinical isolates of Staphylococcus aureus (S. aureus) and Enterococcus faecium (E. faecium) as well as an improved resistance profile in vitro when compared to FA. Importantly, this new compound displays efficacy against an FA-resistant strain of S. aureus in a soft-tissue murine infection model. This work delineates the structural features of FA necessary for potent antibiotic activity and demonstrates that the resistance profile can be improved for this scaffold and target.
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